Rhein is a natural product having an anthraquinone scaffold. It is isolated from the ground plant Rhubarb, which belongs to the Rheum family. A number of anthraquinone compounds isolated form Rheum, such as emodin, have been investigated.
Rhein, and derivatives thereof, are believed to be non-covalent DNA binding drugs. In general, DNA intercalators have common structural features, such as a planar polycyclic aromatic system with different side chains that can vary from simple amines to different sugars. Intercalators can bind within the minor or the major grove of the DNA duplex. Upon binding they may induce conformational changes or even rupture the DNA helix, which can cause cell apoptosis. Another possible mechanism of action is the inhibition of enzymes that bind to the DNA, which may disrupt DNA replication, transcription, etc.
Compounds have an anthraquinone core, similar to rhein, such as doxorubicin and mitoxanthrone, have been marketed as anticancer drugs. These compounds exhibit anticancer activity; however, they have shown serious cardiotoxicity side effects. Studies have shown that rhein is well tolerated by the human body when used as a laxative, and it has anticancer activities against some tumor cells. However, the anticancer activity of rhein against number of cancer cells has been found to be relatively low with IC50 in the range of 12-120 μM.
Therefore, there exists a need for novel compounds having similar or greater activity than doxorubicin, but with fewer side effects, such as cardiovascular side effects.
Therefore, it is an object of the invention to provide rhein analogs having similar or greater activity than doxorubicin, but with fewer side effects, such as cardiovascular side effects, and methods of making and using thereof.